It is now well accepted that CD8+ T cells play a central role in mediating anti-tumor immunity by recognizing tumor-associated antigens presented on major histocompatibility complex class I by their expressed T cell receptor. Majority of studies on cancer neoantigens have therefore focused on MHC class I restricted antigens recognized by CD8+ T cells. However it is also becoming increasingly clear that CD8+ T cell binding neoantigens are not sufficient for mounting a powerful anti tumor response. The recent paper by Alspach et al. proved that spontaneous and immunotherapy-induced antitumor responses required presence of CD4+ in addition to CD8+ T cells (1).
Multiple studies indicate that CD4+ T cells mediate antitumor effects through mechanisms that vary according to tumor environments whether they act as helper or cytotoxic cells but are ultimately dependent on MHC class II neoantigens. In some instances CD4+ T cells were shown to acquire cytotoxicity activity in vivo in presence of a high level of IL-2 or when IL-2 sequestering T Reg cells were absent (2). A recent investigation reported that cytotoxic CD4+ T cells are particularly abundant among supercentenarians and reached 25% of T cells on average, suggesting they are essential to protect against infections and cancers, contributing to achieve an extended disease-free life expectancy (3). Therefore, with improved understanding of the intricate interactions between cytotoxic and helper CD4+ lymphocytes with tumors and antigen presenting cells, interest is currently focused on MHC class II dependent immune activation mechanisms. MHC class II restricted neoantigens have now the potential to be promising targets of cancer immunotherapies.
(1)Alspach, E. et al. MHC-II neoantigens shape tumour immunity and response to immunotherapy. Nature 574: 696–701 (2019).
(2) Śledzińska, A. et al. Regulatory T Cells Restrain Interleukin-2- and Blimp-1-Dependent Acquisition of Cytotoxic Function by CD4+ T Cells. Immunity. 52(1):151-166 (2020).
(3) Hashimoto K. et al. Single-cell transcriptomics reveals expansion of cytotoxic CD4 T cells in supercentenarians. Proc Natl Acad Sci USA. 116(48):24242-24251 (2019).